Antibody Variable (V) region sequence comparison is a powerful aproach toward determining the structural and genetic basis of antibody specificity. (Recent advances in direct mRNA sequencing provide a rapid and reliable way of determining the primary structure of the V regions of monoclonla antibodies produced by hybridomas and B cell lines or lymphomas.) Comparisons of antibodies with similar specificities can reveal regions of homology that predict which domains, complementarity determining regions are specific residues are important for binding (the current technology for introducing base substitutions into specific cloned DNA sequences provides a powerful way to test these predictions). Knowing the structural basis for a given antibody specificity allows one to assess how this specificity is controlled at the genetic level as comparison of expressed V region nucleic acid sequences to their germline counterparts can disttinguish whether a specificity is derived by somatic mutation or encoded in the germline. These approaches will be used to study antibodies directed to determinants on proteins such as influenza hemagglutinin (HA), the I-E histocompatability antigen (Ia.7), rebonucleoprotein (Sm), and immunoglobuin (IgG). Anti-HA and anti-Ia.7 antibodies will be analysized at different intervals during the response to these proteins to determine the relative contribution of germline encoded specificities and mutationally derived specificities to primary and secondary response, how mutations accumulate during the response, and how mutations influence specificity. The autoantibodies, anti-Sm and anti-IgG (Rheumatoid Factor, RF), derived from autoimmune mice (the inbred strain MRL/rpr,) will be studied to determine the structural basis for these specificities. To fully understand these antibodies, however, they will be compared to the RF and anti-Sm antibodies that are produced by normal mice and comparisons between autoantibodies from autoimmune and normal mice will be made between sets with equivalent fine specificities. Knowing how normal and disease autoantibodies differ in their structure and genetic control will lead to an understanding of the process by which they arise in these different settings. The principles derived from the mouse model for autoimmunue disease will be applied to the human disease.